Project 5

Autoimmune Kidney Disease

£890,000 grant to find cure for autoimmune kidney disease.

Manchester experts are among a team of researchers awarded £890,000 by the Medical Research Council to investigate the link between the body’s immune system and the kidney disease, membranous nephropathy (MN), to try to develop a cure.

Professor Paul Brenchley, Dr Edward Mckenzie and Dr Steve Roberts from The University of Manchester and Central Manchester University Hospitals NHS Foundation Trust (CMFT) have joined forces with colleagues Professor Robert Kleta (University College London), Professor Peter Mathieson (University of Bristol) and Professor Ian Roberts (University of Oxford) to carry out a study of MN, which affects about 1200 adults in the UK.

The condition damages the delicate kidney filters, the glomeruli, causing heavy loss of protein from the blood, and is the major cause of the nephrotic syndrome in adults. Patients are at risk of losing kidney function, and suffer an increased risk of stroke, heart disease and infection. At least a third of MN patients will develop chronic kidney disease and require dialysis or a kidney transplant to stay alive. Frustratingly, the disease recurs in 40% of transplants. Around 100 new cases of MN are diagnosed each year. It affects men more than women, usually in middle age, but the trigger for the disease remains unknown.

“Potent drugs are currently used to suppress the patient’s immune system, which can be effective in around half of MN patients in stopping the disease from progressing,” explained Prof Brenchley. “However, this non-specific treatment has the added risk of causing cancer later in life and increasing the existing cardiovascular risk. Interestingly, about a third of patients can get better without these drugs. The big debate for doctors is which patients to treat, with what drugs and for how long – but as yet there is no consensus.”

The team has established a UK consortium which is leading the way in studying the cause and treatment of MN. They looked at the genetics of MN through a European collaborative study of 556 patients led by Prof Kleta, which identified two genes linked to the disease. Combining their results with research in USA showing that 70% of patients with MN have antibodies to one of these genes, PLA2R, the team has established that the body’s own immune system causes MN and has developed the first ELISA assay to diagnose and monitor the disease.

The grant will enable the researchers to study what triggers some patients to produce antibodies against PLA2R, and whether there is a way to switch off the antibody production. They will investigate the genetic make-up of patients who develop the autoantibody and then either progress to kidney failure or spontaneously recover. Being able to predict whether the patient’s disease will progress or remit will enable doctors to target the drug treatment correctly.

The team will also study all patients with MN who have had a kidney transplant in UK. Up to 40% of these transplant patients suffer a recurrence of MN. By studying the differences between donors and recipients where the disease recurs and where it does not, they hope to discover what genetic factors switch the disease back on.

“If our ideas are correct, we may need to make only a simple change in the transplantation process to prevent MN recurring, but we have to provide the evidence for such a change,” added Prof Brenchley. “We will also be analysing the immune system in the subgroup of patients who recover without drug therapy, to see if we can discover how their immune system re-sets itself and use this knowledge to develop a new therapy.”

Manchester Royal Infirmary, where Professor Brenchley is based, is a centre of excellence for nephrology and transplantation. The research team will study up to 200 patients at the hospital as well patients from across the UK over the next three years. The pilot research studies in Manchester were supported by the local Kidneys for Life Charity (Charity no 505256).

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Kidneys for Life raises money research into kidney disease, transplantation, dialysis and related disease affecting the kidney; direct patient amenities for renal and transplant patients not usually funded; supports education of the renal multi-disciplinary team and patients; support for conferences & workshops relating to kidney disease and the purchase of medical equipment.